Unbiased Metabolomics Links Fatty Acid Pathways to Psychiatric Symptoms in People Living with HIV.

Psychiatric symptoms are prevalent in people living with HIV (PLWH), especially depression, anxiety, impulsivity, and substance use. Various biological mechanisms might play a role in the occurrence of psychiatric symptoms in this population. A hypothesis free, data-driven metabolomics approach can further our understanding of these mechanisms. In this study, we identified metabolic pathways associated with impulsivity, depression and substance use in 157 PLWH. First, Spearman's rank correlations between metabolite feature intensities and psychiatric symptom levels were calculated, while controlling for age, gender and body mass index. Subsequently, a mummichog pathway analysis was performed. Finally, we analyzed which individual metabolites drove the observed effects. In our cohort of PLWH, fatty acid-related pathways were associated with both depressive as well as impulsive symptomatology. Substance use showed most extensive metabolic associations, and was positively associated with short chain fatty acids (SCFA's), and negatively associated with glutamate levels. These findings suggest that PUFA metabolism might be associated with both internalising and externalising symptomatology in PLWH. Furthermore, glutamate and SCFA's-microbiome derivatives with known neuroactive properties-might be involved in substance use in these patients. Future studies should explore potential causal mechanisms involved and whether these findings are HIV-specific.